PROJECT SUMMARY Despite large improvements in global childhood mortality in the last 20 years, an astonishing 5.9 million children died before their fifth birthday in 2015. Three of the top five causes of death are infectious, including pneumonia, diarrhea, and neonatal sepsis. Although extrinsic factors such as vaccination, access to clean water, antibiotics, and accurate diagnostics are targets of current public health campaigns, little is known about the host intrinsic factors that affect susceptibility to these illnesses. In particular, thus far overlooked is the role of a small number of maternal cells and DNA acquired by the fetus during pregnancy, known as maternal microchimerism, in infant infection. This proposal specifically seeks to understand the role of these maternal cells in shaping fetal and infant immune responses and subsequent protection from infectious diseases during childhood. We recently found that children with maternal microchimerism at delivery were more likely to become infected with malaria but, when infected, were less likely to become sick or to be hospitalized as compared to children without maternal microchimerism. This finding may imply a mechanism of natural ?vaccination? whereby children experience infection but are protected from disease. We hypothesize that this effect is the result of maternal regulation of pro-inflammatory fetal and infant immune responses, limiting immune-mediated pathology, and that such regulation may extend to immune responses directed against other infections of global health importance. Using samples and data from a birth cohort from Mali, we propose to identify the factors that determine the acquisition of maternal microchimerism, the ability of maternal cells to modulate the immune phenotype of the fetus and infant, and the role of maternal cells in protection from common childhood infections, including pneumonia and diarrhea. We anticipate that this study will demonstrate that acquired maternal cells influence fetal and infant immune responses, which would have broad implications for perinatal and postnatal infections and response to immunization. In addition, demonstrating that maternal cells provide protection against childhood infections would suggest an evolutionary benefit to maintaining this graft, emphasizing the importance of intergenerational immune interactions. Finally, identification of the factors that predict maternal microchimerism may lead to future targets for intentional modulation of maternal cells as a novel approach to prevent the immune-mediated morbidity and mortality associated with childhood infections of global health importance.